AbstractThe medial ganglionic eminence (MGE) produces both locally-projecting interneurons, which migrate long distances to structures such as the cortex as well as projection neurons that occupy subcortical nuclei. Little is known about what regulates the migratory behavior and axonal projections of these two broad classes of neurons. We find that St18 regulates the migration and morphology of MGE neurons in vitro. Further, genetic loss-of-function of St18 in mice reveals a reduction in projection neurons of the globus pallidus pars externa. St18 functions by influencing cell fate in MGE lineages as we observe a large expansion of nascent cortical interneurons at the expense of putative GPe neurons in St18 null embryos. Downstream of St18, we identified Cbx7, a component of Polycomb repressor complex 1, and find that it is essential for projection neuron-like migration but not morphology. Thus, we identify St18 as a key regulator of projection neuron vs. interneuron identity.